Aida Shuji, Hozumi Masashi, Ichikawa Daiju, Iida Kazuki, Yonemura Yuko, Tabata Noriko, Yamada Taketo, Matsushita Maiko, Sugai Takeshi, Yanagawa Hiroshi, Hattori Yutaka
Clinical Physiology & Therapeutics, Keio University Faculty of Pharmacy, Tokyo, Japan.
IDAC Theranostics Inc., Tokyo, Japan.
Biochem Biophys Res Commun. 2017 Nov 4;493(1):514-520. doi: 10.1016/j.bbrc.2017.08.159. Epub 2017 Sep 1.
Despite the development of new drugs for multiple myeloma (MM), the prognosis of MM patients with high-risk cytogenetic abnormalities such as t (4; 14) and del17p remains poor. We reported that a novel phenylphthalimide derivative, TC11, induced apoptosis of MM cells in vitro and in vivo, and TC11 directly bound to α-tubulin and nucleophosmin-1 (NPM1). However, TC11 showed low water solubility and poor pharmacokinetic properties. Here we synthesized a water-soluble TC11-derivative, PEG(E)-TC11, in which HOEtO-TC11 is pegylated with PEG through an ester bond, and we examined its anti-myeloma activity. We observed that PEG(E)-TC11 and its hydrolyzed product, HOEtO-TC11, induced G2/M arrest and the apoptosis of MM cells. Intraperitoneal administration of PEG(E)-TC11 to xenografted mice revealed improved pharmacokinetic properties and significantly delayed tumor growth. TC11 and its derivatives did not bind to cereblon (CRBN), which is a responsible molecule for thalidomide-induced teratogenicity. These results suggest that PEG(E)-TC11 is a good candidate drug for treating high-risk MM.
尽管针对多发性骨髓瘤（MM）开发了新药，但伴有t（4；14）和del17p等高风险细胞遗传学异常的MM患者预后仍然很差。我们报道了一种新型邻苯二甲酰亚胺衍生物TC11在体外和体内均可诱导MM细胞凋亡，且TC11可直接与α-微管蛋白和核磷蛋白-1（NPM1）结合。然而，TC11的水溶性较低且药代动力学性质较差。在此，我们合成了一种水溶性TC11衍生物PEG(E)-TC11，其中HOEtO-TC11通过酯键与聚乙二醇（PEG）进行聚乙二醇化，并且我们检测了其抗骨髓瘤活性。我们观察到PEG(E)-TC11及其水解产物HOEtO-TC11可诱导MM细胞发生G2/M期阻滞和凋亡。对异种移植小鼠腹腔注射PEG(E)-TC11显示其药代动力学性质得到改善，且肿瘤生长显著延迟。TC11及其衍生物不与沙利度胺致畸作用的相关分子cereblon（CRBN）结合。这些结果表明PEG(E)-TC11是治疗高危MM的良好候选药物。
